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Prefrontal Cortex Stimulation Enhances Fear Extinction Memory in Humans

  • Tommi Raij
    Correspondence
    Address correspondence to Tommi Raij, M.D., Ph.D., Center for Brain Stimulation, Shirley Ryan AbilityLab/Northwestern University, 355 East Erie Street, Chicago, IL 60611
    Affiliations
    Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Massachusetts Institute of Technology, Charlestown, Massachusetts

    Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Aapo Nummenmaa
    Affiliations
    Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Massachusetts Institute of Technology, Charlestown, Massachusetts

    Harvard Medical School, Boston, Massachusetts
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  • Marie-France Marin
    Affiliations
    Harvard Medical School, Boston, Massachusetts

    Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
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  • Daria Porter
    Affiliations
    Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
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  • Sharon Furtak
    Affiliations
    Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
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  • Kawin Setsompop
    Affiliations
    Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Massachusetts Institute of Technology, Charlestown, Massachusetts

    Harvard Medical School, Boston, Massachusetts
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  • Mohammed R. Milad
    Correspondence
    Mohammed Milad, Ph.D., Department of Psychiatry, University of Illinois at Chicago, 1747 West Roosevelt Road, Chicago, IL 60608.
    Affiliations
    Harvard Medical School, Boston, Massachusetts

    Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
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Published:November 06, 2017DOI:https://doi.org/10.1016/j.biopsych.2017.10.022

      Abstract

      Background

      Animal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translated this finding to humans with magnetic resonance imaging–navigated transcranial magnetic stimulation (TMS).

      Methods

      Subjects (N = 28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat infralimbic cortex: brief pulse trains (300 ms at 20 Hz) starting 100 ms after cue onset, total of four trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (target 1) and the other unconnected (target 2, control) with a human homologue of infralimbic cortex in the ventromedial prefrontal cortex. Skin conductance responses were used as an index of conditioned fear.

      Results

      During extinction recall (day 3), the cue paired with TMS to target 1 showed significantly reduced skin conductance responses, whereas TMS to target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion magnetic resonance imaging connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced versus increased fear.

      Conclusions

      The results showed that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory and suggested novel cortical areas and large-scale networks for targeting in future studies.

      Keywords

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